Cancer health disparities represent a major public health concern in the United States. Even when socioeconomic factors are accounted for, minority populations have higher overall incidence rates and worse outcomes than the overall population. Prostate cancer is one such disease with higher incidence and death rates in African American (AA) men than Caucasians. Although socioeconomic factors may be blamed to a certain extent, it is appreciated that the genetic composition makes AA men more susceptible to aggressive prostate cancer. Genetic and epigenetic changes are known as tumorigenic drivers because epigenetic editing precludes mounting of host antitumor response necessary for tumor cell clearance. DNA methylation, catalyzed by DNA methyltransferase (DNMT), is the best-characterized epigenetic modification in prostate cancer, and racial disparities in DNA methylation are associated with cancer prognosis and survival. Therefore, targeting of DNMT to reverse epigenetic alterations is an appealing therapeutic target, and vital to reduce the observed prostate cancer outcome gaps among AA men and Caucasians. The deoxycytidine analogue decitabine is unique in that it can be repositioned for non-cytotoxic depletion of DNMT. We characterized a low dose of decitabine with its increased absorption in the presence of tetrahydrouridine (THU). Combination of THU with decitabine changes its pharmacology, and facilitates non-cytotoxic DNMT1 depletion. We demonstrated that the THU-decitabine combination significantly inhibits the growth of TRAMP-C2 prostate tumors in immune competent mice, and the addition of CpG immunotherapy further enhanced antitumor immunity. Based on our strong preliminary data, we hypothesize that THU-decitabine directed epigenetic therapy revitalize the host intrinsic immunity and augment vaccine-induced antitumor response. Since DNA methylation is prevalent and relates to greater risk in AAs, DNMT depletion will invigorate the immune response of tumor-bearing host, providing an opportunity to immunotherapy inducing robust antitumor immunity. We will test the combination of THU-decitabine directed DNMT depletion, immune modulation and therapeutic vaccine to determine 1) the effect of epigenetic editing on prostate cancer cell growth in murine models; and 2) the effector mechanism of THU-decitabine guided vaccine- induced antigen-specific antitumor immunity in complete regression of early and advanced castration-resistant prostate cancer. This project is novel because the concept of a non-toxic THU-decitabine combination with immunotherapy has not been tested in any cancer type. This combinatorial approach will significantly attenuate the growth of aggressive prostate cancer as often presented in AA men, and may represent a novel treatment to reduce prostate cancer disparity.